Celastrol attenuates hepatitis C virus translation and inflammatory response in mice by suppressing heat shock protein 90ß.

Hepatitis C virus (HCV) infection is one of the major factors to trigger a sustained hepatic inflammatory response and hence hepatocellular carcinoma (HCC), but direct-acting-antiviral (DAAs) was not efficient to suppress HCC development. Heat shock protein 90 kDa (HSP90) is highly abundant in different types of cancers, and especially controls protein translation, endoplasmic reticulum stress, and viral replication. In this study we investigated the correlation between the expression levels of HSP90 isoforms and inflammatory response marker NLRP3 in different types of HCC patients as well as the effect of a natural product celastrol in suppression of HCV translation and associated inflammatory response in vivo. We identified that the expression level of HSP90ß isoform was correlated with that of NLRP3 in the liver tissues of HCV positive HCC patients (R2 = 0.3867, P < 0.0101), but not in hepatitis B virus-associated HCC or cirrhosis patients. We demonstrated that celastrol (3, 10, 30 µM) dose-dependently suppressed the ATPase activity of both HSP90α and HSP90ß, while its anti-HCV activity was dependent on the Ala47 residue in the ATPase pocket of HSP90ß. Celastrol (200 nM) halted HCV internal ribosomal entry site (IRES)-mediated translation at the initial step by disrupting the association between HSP90ß and 4EBP1. The inhibitory activity of celastrol on HCV RNA-dependent RNA polymerase (RdRp)-triggered inflammatory response also depended on the Ala47 residue of HSP90ß. Intravenous injection of adenovirus expressing HCV NS5B (pAde-NS5B) in mice induced severe hepatic inflammatory response characterized by significantly increased infiltration of immune cells and hepatic expression level of Nlrp3, which was dose-dependently ameliorated by pretreatment with celastrol (0.2, 0.5 mg/kg, i.p.). This study reveals a fundamental role of HSP90ß in governing HCV IRES-mediated translation as well as hepatic inflammation, and celastrol as a novel inhibitor of HCV translation and associated inflammation by specifically targeting HSP90ß, which could be developed as a lead for the treatment of HSP90ß positive HCV-associated HCC.

SIRT1 Protects Against Oxidative Stress-Induced Endothelial Progenitor Cells Apoptosis by Inhibiting FOXO3a via FOXO3a Ubiquitination and Degradation.

Cell loss due to apoptosis induced by oxidative stress is a major hurdle for endothelial progenitor cells (EPCs)-based therapy. Sirtuin 1 (SIRT1) plays important roles in many pathophysiological processes by deacetylating various substrates, including forkhead transcription factor (FOXO). However, after deacetylation, the fate of FOXO protein remains to be explored. In the present study, we investigated whether SIRT1 exerted a protective effect on hydrogen peroxide (H(2)O(2))-induced EPCs apoptosis and, if so, what the underlying mechanism might be. EPCs were isolated and obtained from human umbilical cord blood by density gradient centrifugation and identified by morphology, tube formation ability, cell surface markers, and the ability to take up acetylated low-density lipoprotein (Dil-Ac-LDL) and bind ulex europaeus agglutinin 1 (FITC-UEA-1). Immunofluorescence showed that SIRT1 is localized in the nucleus of EPCs in the presence or absence of H(2)O(2). SIRT1 protein level in EPCs was increased by the treatment with H(2)O(2) for 24 h. Incubation of EPCs with H(2)O(2) dose dependently induced EPCs apoptosis. SIRT1 overexpression reduced the rate of EPCs apoptosis induced by H(2)O(2), whereas SIRT1 downregulation and EX527, a specific SIRT1 inhibitor, exerted the opposite effect. SIRT1 overexpression decreased the total FOXO3a protein expression, whereas SIRT1 downregulation and EX527 increased the amount of FOXO3a protein. SIRT1 reduced FOXO3a transcriptional activity according to Bim expression. Co-immunoprecipitation assay showed that SIRT1 could bind to FOXO3a, reduce its acetylation level and increase its ubiquitination level. To sum up, our work demonstrated that SIRT1 had a pivotally protective role in the regulation of EPCs apoptosis induced by H(2)O(2) and that SIRT1 protected against apoptosis by inhibiting FOXO3a via FOXO3a ubiquitination and subsequent degradation.

Erythrocyte-Mimicking Nanovesicle Targeting Porphyromonas gingivalis for Periodontitis.

Porphyromonas gingivalis has been demonstrated to have the strongest association with periodontitis. Within the host, P. gingivalis relies on acquiring iron and heme through the aggregation and lysis of erythrocytes, which are important factors in the growth and virulence of P. gingivalis. Additionally, the excess obtained heme is deposited on the surface of P. gingivalis, protecting the cells from oxidative damage. Based on these biological properties of the interaction between P. gingivalis and erythrocytes, this study developed an erythrocyte membrane nanovesicle loaded with gallium porphyrins to mimic erythrocytes. The nanovesicle can target and adhere with P. gingivalis precisely, being lysed and utilized by P. gingivalis as erythrocytes. Ingested gallium porphyrin replaces iron porphyrin in P. gingivalis, causing intracellular metabolic disruption. Deposited porphyrin generates a large amount of reactive oxygen species (ROS) under blue light, causing oxidative damage, and its lethality is enhanced by bacterial metabolic disruption, synergistically killing P. gingivalis. Our results demonstrate that this strategy can target and inhibit P. gingivalis, reduce its invasion of epithelial cells, and alleviate the progression of periodontitis.

A novel andrographolide derivative AL-1 exerts its cytotoxicity on K562 cells through a ROS-dependent mechanism.

Andrographolide-lipoic acid conjugate (AL-1) is a new in-house synthesized chemical entity, which was derived by covalently linking andrographolide with lipoic acid. However, its anti-cancer effect and cytotoxic mechanism remains unknown. In this study, we found that AL-1 could significantly inhibit cell viability of human leukemia K562 cells by inducing G2/M arrest and apoptosis in a dose-dependent manner. Thirty-one AL-1-regulated protein alterations were identified by proteomics analysis. Gene ontology and ingenuity pathway analysis revealed that a cluster of proteins of oxidative redox state and apoptotic cell death-related proteins, such as PRDX2, PRDX3, PRDX6, TXNRD1, and GLRX3, were regulated by AL-1. Functional studies confirmed that AL-1 induced apoptosis of K562 cells through a ROS-dependent mechanism, and anti-oxidant, N-acetyl-L-cysteine, could completely block AL-1-induced cytotoxicity, implicating that ROS generation played a vital role in AL-1 cytotoxicity. Accumulated ROS resulted in oxidative DNA damage and subsequent G2/M arrest and mitochondrial-mediated apoptosis. The current work reveals that a novel andrographolide derivative AL-1 exerts its anticancer cytotoxicity through a ROS-dependent DNA damage and mitochondrial-mediated apoptosis mechanism.

Hydrogen peroxide induced impairment of endothelial progenitor cell viability is mediated through a FoxO3a dependant mechanism.

OBJECTIVES: Increased oxidative stress has been suggested to contribute to the functional impairment of endothelial progenitor cells (EPCs). The Forkhead box O transcription factors (FoxOs) are critical regulators involved in various cellular processes including cell apoptosis. Here, we investigated whether FoxOs are required in oxidative stress induced EPC apoptosis. METHODS AND RESULTS: EPCs were cultured from cord blood derived mononuclear cells and treated with hydrogen peroxide (H2O2) for induction of oxidative stress. Incubation with H2O2 dose dependently reduced viability and increased apoptosis in EPCs. Western blotting showed that EPCs predominantly expressed FoxO3a and the expression was markedly increased upon H2O2 treatment. Transduction with adenoviral vectors expressing either a wide-type or a non-phosphorylatable, constitutively active mutant of FoxO3a led to further increased apoptosis of EPCs after H2O2 treatment. Conversely, FoxO3a silencing rescued EPCs from these H2O2 induced deleterious effects. Overexpression of FoxO3a also increased the level of the pro-apoptotic protein Bim, whereas FoxO3a silencing downregulated H2O2 induced Bim expression. Furthermore, Matrigel assay demonstrated that FoxO3a overexpression significantly impaired the tube forming ability of EPCs, whereas its silencing completely protected EPCs from H2O2 induced decrease of capillary formation. CONCLUSIONS: These data suggest that oxidative stress induced impairment of EPC survival is mediated through a FoxO3a dependant mechanism, possibly by transcriptional regulation of Bim. Our data indicate FoxO3a as a potential therapeutic target for improvement of EPC number and function in patients with ischemic heart disease.

The effects of temperature on the development of the moth Athetis lepigone, and a prediction of field occurrence.

Athetis lepigone (Möschler) (Lepidoptera: Noctuidae) is an important insect pest of corn crops in China. To determine the effect of temperature on A. lepigone growth, and to provide a forecasting model for this pest, the development and fecundity of A. lepigone under five different temperatures (18, 21, 24, 27, 30 °C) was investigated, and an experimental population life table was constructed based on the obtained results. The results showed that the duration of development of A. lepigone decreased as the temperature increased from 18 to 30 °C. Approximately 95% of mature larvae stopped pupating at 18 °C, and about 70% of mature larvae stopped pupating at 21 °C. When the growth chamber temperature was above 24 °C, no growth arrest was observed. The results indicated that the optimum growth temperature of A. lepigone was about 26.47 °C. In this study, the highest survival rate, fecundity per female, and population index trend were observed when the temperature was set at 27 °C. The percentages of larvae that could spin cocoons after the 5th or 6th instar differed at the different temperatures. The developmental threshold temperatures for A. lepigone eggs, larvae, pre-pupae, pupae, preoviposition females, and the whole generation (i.e., egg to oviposition) were 11.03, 9.04, 15.08, 11.79, 11.63, and 10.84 °C, respectively, and their effective accumulative temperatures were 63.51, 339.42, 30.04, 118.41, 35.06 and 574.08 degree-days, respectively. Based on the effective accumulative temperature law, this pest insect can have four generations in most of the Huang-Huai region of China, and two to three generations annually in some cold regions. Athetis lepigone may have four generations in the mid-southern part of Hebei Province. This prediction matches the field survey results.

Effect of preoperative inspiratory muscle training on postoperative outcomes in patients undergoing cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: Cardiovascular disease is the most prevalent disease worldwide and places a great burden on the health and economic welfare of patients. Cardiac surgery is an important way to treat cardiovascular disease, but it can prolong mechanical ventilation time, intensive care unit (ICU) stay, and postoperative hospitalization for patients. Previous studies have demonstrated that preoperative inspiratory muscle training could decrease the incidence of postoperative pulmonary complications. AIM: To explore the effect of preoperative inspiratory muscle training on mechanical ventilation time, length of ICU stay, and duration of postoperative hospitalization after cardiac surgery. METHODS: A literature search of PubMed, Web of Science, Cochrane Library, EMBASE, China National Knowledge Infrastructure, WanFang, and the China Science and Technology journal VIP database was performed on April 13, 2022. The data was independently extracted by two authors. The inclusion criteria were: (1) Randomized controlled trial; (2) Accessible as a full paper; (3) Patients who received cardiac surgery; (4) Preoperative inspiratory muscle training was implemented in these patients; (5) The study reported at least one of the following: Mechanical ventilation time, length of ICU stay, and/or duration of postoperative hospitalization; and (6) In English language. RESULTS: We analyzed six randomized controlled trials with a total of 925 participants. The pooled mean difference of mechanical ventilation time was -0.45 h [95% confidence interval (CI): -1.59-0.69], which was not statistically significant between the intervention group and the control group. The pooled mean difference of length of ICU stay was 0.44 h (95%CI: -0.58-1.45). The pooled mean difference of postoperative hospitalization was -1.77 d in the intervention group vs the control group [95%CI: -2.41-(-1.12)]. CONCLUSION: Preoperative inspiratory muscle training may decrease the duration of postoperative hospitalization for patients undergoing cardiac surgery. More high-quality studies are needed to confirm our conclusion.

Postoperative Pulmonary Complications in Patients With Transcatheter Tricuspid Valve Implantation-Implications for Physiotherapists.

Objectives: To investigate the incidence of postoperative pulmonary complications (PPCs) and short-term recovery after transcatheter tricuspid valve implantation (TTVI). Methods: A total of 17 patients diagnosed with severe tricuspid regurgitation who received a LuX-valve TTVI were included in this study. Spirometry lung function, maximal inspiratory pressure (MIP), and 6-min walk test distance (6MWD) were recorded. Prior to surgery, patients were stratified into high or low pulmonary risk groups based on published predefined criteria. A physiotherapist provided all patients with education on thoracic expansion exercises, effective cough and an inspiratory muscle training protocol at 50% of MIP for 3 days preoperatively. All patients received standard post-operative physiotherapy intervention including positioning, thoracic expansion exercises, secretion removal techniques and mobilization. Patients were assessed for PPCs as defined by the Melbourne-Group Score-version 2. Clinical characteristics and hospital stay, cost, functional capacity, and Kansas City Cardiomyopathy Questionnaire (KCCQ) heart failure score were recorded at admission, 1-week, and 30-days post-op. Results: The mean (SD) age of the 17 patients was 68.4 (8.0) years and 15 (88%) were female. Pre-surgical assessment identified 8 patients (47%) at high risk of PPCs. A total of 9 patients (53%) developed PPCs between the 1st and 3rd day post-surgery, and 7 of these 9 patients were amongst the 8 predicted as "high risk" prior to surgery. One patient died before the 30 day follow up. Pre-operative pulmonary risk assessment score, diabetes mellitus, a low baseline MIP and 6MWD were associated with a high incidence of PPCs. Compared to those without PPCs, patients with PPCs had longer ICU and hospital stay, and higher hospitalization cost. At 30 days post-surgery, patients without PPCs maintained higher MIP and 6MWD compared to those with PPCs, but there were no significant between-group differences in other lung function parameters nor KCCQ. Conclusion: This is the first study to report the incidence of PPCs post TTVI. Despite a 3-day prehabilitation protocol and standard post-operative physiotherapy, PPCs were common among patients after TTVI and significantly impacted on hospital and short-term recovery and outcomes. In the majority of patients, PPCs could be accurately predicted before surgery. A comprehensive prehabilitation program should be considered for patients prior to TTVI. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [ChiCTR2000039671].

Synthesis and preliminary evaluation of anti-HIV agent AZT prodrug.

In this research, phosphate and thiophosphate prodrugs 3a, 3b of anti-HIV agent AZT were synthesized, and their anti-HIV activities and cytotoxicities were investigated in vitro. Results showed that the prodrugs 3a and 3b with an IC50 value of 11.0 and 4.0 micromol x L(-1), respectively, were less toxic than AZT (1.0 micromol x L(-1)). Although the EC50 values of both 3a (0.04 micromol x (L(-1) and 3b (0.16 micromol x L(-1)) were lower than that of AZT (0.01 micromol x L(-1)), the therapeutic index (IC50/EC50) of prodrug 3a (275) was much higher than that of both AZT (100) and prodrug 3b (25). This indicated that the prodrug 3a merited further investigation as an anti-HIV agent.

[Pharmacokinetics studies on tetramethylpyrazine by intravenous administration in rats].

OBJECTIVE: To investigate the pharmacokinetics behaviour of tetramethylpyrazine (TMP) by intravenous administration in rats. METHODS: Methanol-0.05 mol/L acetate buffer solution (50:50,V/V) was used as mobile phase with a flow rate of 1.0 mL/min. The UV detection wavelength was 280 nm. RESULTS: The profile of TMP in blood fitted a two-compartment model. The half time of drug distribution and elimination was short. The mean residence time MRT 0-infinity was 141.61 min, and the AUC0-infinity was 7521.70 microg x min/ mL. CONCLUSION: After intravenous injection, the pharmacokinetics behaviour of TMP fit a two-compartment model in rats. Both the distribution and the elimination are fast.

[Inhibitory effect of TBN on platelet aggregation in rabbit].

OBJECTIVE: To investigate the inhibitory effect of TBN on rabbit platelet aggregation in vitro and in vivo, and compare with tetramethylpyrazine (TMP). METHODS: To seek out the maximum of platelet aggregation (expressed in percentage) within 5 minutes which was induced by ADP, PAF and AA according to the Born turbidimetric method with a Platelet-Aggregometer. RESULTS: TBN significantly inhibited platelet aggregation induced by ADP, PAF and AA both in vitro and in vivo. TBN was more active than TMP. CONCLUSION: TBN has significant activity inhibiting platelet aggregation induced by ADP, PAF and AA in vitro and in vivo.

Activity of andrographolide and its derivatives against influenza virus in vivo and in vitro.

Infections with influenza A viruses are still a major threat to humans and several animal species. The occurrence of highly pathogenic avian influenza viruses capable of infecting and killing humans highlights the urgency for a new and efficient strategy for the treatment of diseases caused by the virus. Andrographolide and its derivatives have been widely used for treating respiratory infections in China for decades. We have recently synthesized new andrographolide derivatives and found that some of the compounds including 14-alpha-lipoyl andrographolide (AL-1) have significant activity against bacterial infections with an unique mechanism of action. We report here the antiviral activity of AL-1 and other andrographolide drugs. AL-1 showed significant activity against influenza A viruses including the H5N1 avian influenza virus. The administration of AL-1 by oral gavage to mice infected with avian influenza A/Chicken/Guangdong /96 (H9N2), A/Duck/Guangdong/99 (H5N1), and human influenza A/PR/8/34 (H1N1) viruses greatly reduced the death rate, prolonged life, inhibited lung consolidation, and reduced viral titers in the lung. The most effective dosage of AL-1 in these studies ranged from 100 to 200 mg/kg/d, when administered twice daily for 7 d beginning 24 h before viral exposure. The LD(50) of AL-1 was 1243 mg/kg/d. AL-1 was effective against avian influenza A (H9N2 and H5N1) and human influenza A H1N1 viruses in vitro, with the 50% effective concentrations ranging from 7.2 to 15.2 microM and the selective indexes ranging from 51 to 109. Significant inhibition of viral adsorption onto red blood cells with minimum inhibitory concentrations ranging from 5.3 to 16.8 mM suggested that AL-1 was capable of directly interfering with viral hemagglutinin to block binding to cellular receptors. With potent antiviral activity and a potentially new mechanism of action, AL-1 may warrant further evaluation as a possible therapy for influenza.

Progress of titanium strut for cervical reconstruction with nano-graphene oxide loaded hydroxyapatite/polyamide composite and interbody fusion after corpectomy with anterior plate fixation.

To evaluate the long-term biological and clinical results of anterior cervical corpectomy and fusion (ACCF) with a synthesized nano-graphene oxide (nano-GO) loaded hydroxyapatite/polyamide (HAp/PA) strut in the implantation treatment of cervical reconstruction. Bio-ceramic Hydroxyapatite (HAp) combined with suitable polymer matrix is one of the furthermost naturally occurring biomaterial form for hard tissues and dental regeneration therapies due to their bone-like chemical compositional structure and biocompatibility similarity to native bone of the human body. In the present investigation, the development of nano-GO loaded HAp/PA composite strut for anterior cervical reform and fusion properties after corpectomy is studied. Forty patients who suffered from first or second level ACCF, treated with nano-GO loaded HAp/PA strut, were investigated. At final follow-up period, the fusion rate was 99%, and the subsidence value of the prepared strut was 5%. The results of cell viability and proliferation analyses indicated that the prepared nanocomposites did not exhibit non-cytotoxicity with the human cells. In summary, the satisfactory consequences in this research work designated that the nano-GO loaded HAp/PA strut was an active implant in the treatment of cervical reconstruction. Furthermore, the osteoconductive and osseointegration properties of the prepared struts need to be analyzed and optimized for future bio-medical usages.

Andrographolide derivative ameliorates dextran sulfate sodium-induced experimental colitis in mice.

The therapeutic efficacy of immunosuppressive agents has been intensively studied for colitis management. We synthesized a series of andrographolide derivatives and reported their structure-activity-relationship and anti-inflammatory activity in our previous studies. Among these derivatives, compound 3b exhibited the most potent immunosuppressive activity. In the present study, we assessed the efficacy of 3b in dextran sulfate sodium (DSS)-induced model of acute colitis. Compound 3b was administered intragastrically. The therapeutic effect of 3b was evaluated using disease score and immune cell infiltration. The effect of 3b on Toll-like receptor 4/NF-κB and ß-catenin signaling was primarily determined by using immunohistochemistry staining and quantitative real-time PCR. The crosstalk between NF-κB and ß-catenin signaling was then assessed in HCT-116 cells. Treatment with 3b significantly downregulated the disease activity index and suppressed the histologic evidence of inflammation in DSS-induced model of acute colitis. Compound 3b inhibited proinflammatory cytokine expression at both the serum and transcription levels. Treatment with 3b also upregulated the number of PCNA-positive and goblet cells in the intestinal crypt and the intestinal expression of mRNA levels of ß-catenin target genes. ß-Catenin level regulation affected the antiinflammation and anti-apoptotic activities of 3b. This study demonstrated that 3b, a novel andrographolide derivative, suppressed inflammation and significantly reversed colitis pathology. The outcome of colitis treatment with an immunosuppressive agent depends upon the intestinal expression and mutation status of ß-catenin.

Degradation kinetics of water-insoluble lauroyl-indapamide in aqueous solutions: prediction of the stabilities of the drug in liposomes.

The aim of this study was to explore the degradation kinetics of water-insoluble lauroyl-indapamide in solutions and predict the stabilities of lauroyl-indapamide encapsulated in liposomes. Buffer-acetone (9:1) was used as the reaction solution and the reaction temperature was maintained at 60 degrees C. The correlation of the apparent degradation constants (k(obs)) of lauroyl-indapamide in liposomes and in buffer-acetone solutions at different pH has been explored. The degradation of lauroyl-indapamide in solutions was found to follow pseudo-first-order kinetics and was significantly dependent on the pH values. Lauroyl-indapamide was the most stable at pH 6.8, increasing or decreasing the pH of the solutions would decrease its stabilities. Buffer concentration had some effects on the stabilities of lauroyl-indapamide. The degradation active energies Ea were 68.19 kJ x mol(-1), 131.75 kJ x mol(-1) and 107.72 kJ x mol(-1) at pH3.6, 6.8 and 12 respectively in acetone-free buffer solutions (0.05M) calculated according to the Arrhenius equation with the extrapolation method. The apparent degradation constants (kobs) of lauroyl-indapamide in liposome and in buffer-acetone (9:1) solutions showed a good correlation at different pH levels, which indicates that the stabilities of the drug that dissolved in acetone-buffer mixture solutions can be used to predict the stabilities of the drug in liposomes as well.

[Study on effect of Xianzhong Injection on morphology of knee and insulin-like growth factor-1 in rabbits with early stage osteoarthritis].

OBJECTIVE: To investigate the effect of Xianzhong Injection (XI) on morphology of knee and insulin-like growth factor-1 (IGF-1) in rabbits with early stage osteoarthritis (OA). METHODS: One hundred and twenty rabbits were randomly divided into 5 groups, the blank group, the model group treated with 0.5 mL normal saline once a week, the positive control group treated with 0.5 mL hyaluronate once a week, and the XI 1 group and XI 2 group with 0.5 mL XI once and twice a week, respectively, all the medicines were medicated via intra-articular injection. Knee joint function was examined 8 weeks after modeling, IGF-1 content in serum and synovia was detected, and the histologic examination of articular cartilage was observed by Mallory staining as well. RESULTS: The improvement of knee joint function was better in the XI 1 and 2 groups than that in the model group (P < 0.01), and that in the XI 1 group was equivalent to that in the positive control group (P > 0.05). Histologic examination showed there was no calcification in all the layers of cartilage in the positive control group and the XI 1 group with complete cartilaginous bluish-green collagen preserved. The content of IGF-1 increased in synovia and serum in the positive control group and the two XI groups as compared with that in the model group (P < 0.05). CONCLUSION: XI can improve knee joint function to certain extent in early OA, and repair the degenerative cartilage.

[Clinical observation on effect of xian-zhong injection on treating primary knee OA].

OBJECTIVE: To research and evaluate the clinical efficacy of Xian-zhong injection in treating primary knee OA. METHODS: By using Lequesne instituted ISOA and Kellgren-Lawrance instituted X-ray class standard, 127 non-operation primaary knee OA patients were divided into three grades (Light, Moderate, Severe). To adopt randomized single controlled trial, each grade was divided into two groups, respectively injected Xian-zhong injection or Sodium Hyaluronate injection. Every injection's volume was 2 ml and injected one per week, then consecutively injected one month. Finally we followed up in the first month, third month, sixth month, afterward we did every six months. RESULTS: After followed up one - twenty-four months we found ISOA score less than thirteen and K-LA X-ray class standard less than III grade, the clinical efficacy of two kind of injections was better. But ISOA score more than thirteen and K-LA X-ray class standard mord than III grade, the clinical efficacy was bad. The follow-up showed that the total effective rate and excellent rate between Xian-zhong injection group and Sodium Hyaluronate injection group weren't significantly different. CONCLUSION: Xian-zhong injection can improve the clinical efficacy of primary knee OA, it has the greatest researching value and using furthermore.

No synergism between bis(propyl)-cognitin and rasagiline on protecting dopaminergic neurons in Parkinson's disease mice.

Rasagiline, a monoamine oxidase-B inhibitor, and bis(propyl)-cognitin (B3C), a novel dimer are reported to be neuroprotective. Herein, the synergistical neuroprotection produced by rasagiline and B3C was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice of Parkinsonism. By using neurobehavioural tests, high-performance liquid chromatography and western blot assay, we showed that B3C at 0.3 mg/kg, rasagiline at 0.02 mg/kg, as well as co-treatment with B3C and rasagiline prevented MPTP-induced behavioural abnormities, increased the concentrations of dopamine and its metabolites in the striatum, and up-regulated the expression of tyrosine hydroxylase in the substantia nigra. However, the neuroprotective effects of co-treatment were not significantly improved when compared with those of B3C or rasagiline alone. Collectively, we have demonstrated that B3C at 0.3 mg/kg and rasagline at 0.02 mg/kg could not produce synergistic neuroprotective effects.

Nanoparticle-mediated RNA interference of angiotensinogen decreases blood pressure and improves myocardial remodeling in spontaneously hypertensive rats.

Angiotensinogen (AGT) has been shown to have a role in cardiac hypertrophy, while depletion of the AGT gene in spontaneously hypertensive rats (SHR) has not been investigated. The present study investigated the effect of AGT knockdown on cardiac hypertrophy in SHR. For this, small hairpin (sh)RNAs were intravenously injected into SHRs, using a nanoparticle­mediated transfection system. The experimental rats were divided into the following groups: a) Blank control with water treatment only, b) negative control with biscarbamate­crosslinked Gal­polyethylene glycol polyethylenimine nanoparticles (GPE)/negative shRNA, c) AGT­RNA interference (RNAi) group with GPE/AGT­shRNA, and 4) normotensive control using Wistar­Kyoto rats (WKY) with water treatment. Three and five days following the first injection, the levels of hepatic AGT mRNA and AGT protein as well as plasma levels of AGT were markedly decreased in the AGT­RNAi group (P<0.05). Furthermore, a significant decrease in systolic blood pressure (SBP), left ventricular weight to body weight ratio and heart weight to body weight ratio were observed in the AGT­RNAi group compared with those in the control groups. The depletion of AGT in SHR led to a reduction in SBP by 30±4 mmHg, which was retained for >10 days. Cardiac hypertrophy was also significantly improved in AGT­knockdown rats. In conclusion, the present study showed that AGT­silencing had a significant inhibitory effect on hypertension and hypertensive­induced cardiac hypertrophy in SHRs.

A Potent Multi-functional Neuroprotective Derivative of Tetramethylpyrazine.

Neurodegenerative disorders are one of the leading causes of death among the elderly. Therapeutic approaches with a single target have proven unsuccessful in treating these diseases. Structural combination of multi-functional compounds may lead to a molecule with multiple properties. In this study, we designed and synthesized T-006, a novel analog derived from two multi-functional neuroprotective chemicals, tetramethylpyrazine and J147. The methoxyphenyl group of J147 was replaced by tetramethylpyrazine. Bioactivity evaluation showed that T-006 at very low concentrations had multi-functional neuroprotective effects including rescuing iodoacetic acid-induced neuronal loss, preventing oxidative stress-induced neurotoxicity and reducing glutamate-induced excitotoxicity in vitro. Most importantly, T-006 significantly ameliorated memory impairments in APP/PS1 transgenic mice. These multiple functions of a single molecule suggest that T-006 is a promising novel neuroprotective agent for treating various neurodegenerative disorders, including and in particular Alzheimer's disease.